Proarrhythmic effect of sustained EPAC activation on TRPC3/4 in rat ventricular cardiomyocytes

• Published in: Journal of molecular and cellular cardiology 2015-10, Vol.87, p.74-78
• Main Authors: Domínguez-Rodríguez, Alejandro, Ruiz-Hurtado, Gema, Sabourin, Jessica, Gómez, Ana Maria, Alvarez, Julio L, Benitah, Jean-Pierre
• Format: Article
• Language: English
• Subjects: Animals; Benzene Derivatives - administration & dosage; Calcium - metabolism; Calcium Signaling - drug effects; Cardiomegaly - drug therapy; Cardiomegaly - genetics; Cardiomegaly - pathology; Cardiomyocyte; Cardiovascular; Complement C4 - biosynthesis; Complement C4 - genetics; Cyclic AMP - metabolism; Cyclic GMP - administration & dosage; Cyclic GMP - analogs & derivatives; Exchange Protein directly Activated by Cyclic AMP (EPAC); Guanine Nucleotide Exchange Factors - biosynthesis; Guanine Nucleotide Exchange Factors - genetics; Heart Ventricles - metabolism; Heart Ventricles - pathology; Humans; Life Sciences; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Quinolines - administration & dosage; Rats; Store-Operated Ca2+ Entry (SOCE); Sulfones - administration & dosage; Thionucleotides - administration & dosage; Transient Receptor Potential Canonical (TRPC) channels; TRPC Cation Channels - antagonists & inhibitors; TRPC Cation Channels - genetics
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2015.07.002

Abstract The Exchange Protein directly Activated by cAMP (EPAC) participates to the pathological signaling of cardiac hypertrophy and heart failure, in which the role of Ca2+ entry through the Transient Receptor Potential Canonical (TRPC) channels begin to be appreciated. Here we studied whether EPAC activation could influence the activity and/or expression of TRPC channels in cardiac myocytes. In adult rat ventricular myocytes treated for 4 to 6 h with the selective EPAC activator, 8-pCPT (10 μM), we observed by Fluo-3 confocal fluorescence a Store-Operated Ca2+ Entry (SOCE) like-activity, which was blunted by co-incubation with EPAC inhibitors (ESI-05 and CE3F4 at 10 μM). This SOCE-like activity, which was very small in control incubated cells, was sensitive to 30-μM SKF-96365. Molecular screening showed a specific upregulation of TRPC3 and C4 protein isoforms after 8-pCPT treatment. Moreover, sustained EPAC activation favored proarrhythmic Ca2+ waves, which were reduced either by co-incubation with EPAC inhibitors or bath perfusion with TRPC inhibitors. Our study provides the first evidence that sustained selective EPAC activation leads to an increase in TRPC3 and C4 protein expression and induces a proarrhythmic SOCE-like activity in adult rat ventricular cardiomyocytes, which might be of importance during the development of cardiac diseases.